When Judy Crawford encounters challenging scientific information, her brain translates it to
"binary...quotient...parallelogram." Genetics can be intimidating to licensed practitioners, and a common response is to ignore this information. What does the MTHFR gene have to do with your clinical practice? Since you are probably not a physician, why should you care?
This post was inspired by stimulating Friday morning chats with Dr. Ron Swatzyna, Director and Chief Scientist of the Houston Neuroscience Brain Center.
Dr. Swatzyna (2024) reviews a patient's family history for miscarriages, and heart issues (not necessarily a heart attack) or strokes before their 70s due to their statistical association with the MTHFR gene's C677T and A1298C polymorphisms (Kim & Becker, 2003; Ray et al., 1999; Xuan et al., 2014). When the family history is positive for any of these disorders, he recommends that the patient purchase a $109 empowerDX genetic test.
Common MTHFR mutations can contribute to psychological disorders like anxiety and depression. When a child experiences functional difficulties or does not perform at their potential, or when treatment does not succeed, your patient's physician can order a blood test for elevated homocysteine levels or a noninvasive genetic test. If positive, they can increase folate in their diet and take methylfolate supplements to correct this deficiency. Methylfolate can modestly augment treatment. DNA graphic © aycan balta/Shutterstock.com.
Introduction
Genetic variations within our DNA can significantly impact how our bodies function, often in ways that are not immediately visible. One such gene that has recently gained attention is the MTHFR gene or methylenetetrahydrofolate reductase. This gene is integral to various bodily functions, particularly those related to brain health and psychological well-being. In this post, we will explore the normal function of the MTHFR gene, the impact of its mutations, the role of genetic testing, dietary interventions, and how these mutations can influence brain activity.
The Normal Function of the MTHFR Gene
The MTHFR gene encodes an enzyme that plays a vital role in processing amino acids, the building blocks of proteins. Specifically, the MTHFR enzyme converts homocysteine, a potentially harmful substance, into methionine, an amino acid essential for various bodily functions, including protein synthesis and the production of crucial molecules (Lucock, 2000). Additionally, the MTHFR enzyme is instrumental in converting folate, a type of B vitamin, into its active form. This active form of folate is necessary for DNA synthesis, repair, and the creation of neurotransmitters—chemical messengers that transmit signals in the brain (Bailey & Gregory, 1999). Under normal circumstances, a properly functioning MTHFR enzyme helps maintain low homocysteine levels. It ensures that folate is active, supporting various essential bodily processes, including brain function (Finkelstein, 2000).
Impact of MTHFR Gene Mutations
This delicate balance can be disrupted when mutations occur in the MTHFR gene. The two most common mutations in this gene are C677T and A1298C. These mutations can significantly reduce the efficiency of the MTHFR enzyme, leading to various downstream effects (Roffman et al., 2008). An increase in homocysteine levels is one of the most immediate consequences of a less efficient MTHFR enzyme. Elevated homocysteine is associated with cardiovascular issues, but it can also have a significant impact on brain health. High homocysteine levels are linked to an increased risk of neurodegenerative diseases and cognitive decline, illustrating how disruptions in the MTHFR gene's function can have widespread effects (Clarke et al., 1998).
In addition, when the MTHFR enzyme's activity is compromised, the body struggles to convert folate into its active form. This can lead to a deficiency in active folate, even if dietary intake is sufficient. Folate is critical for the production of neurotransmitters, and a deficiency can result in imbalances that may contribute to various psychological disorders (Reynolds, 2002).
Research has increasingly explored the connection between MTHFR mutations and psychological conditions, such as depression, anxiety, schizophrenia, and bipolar disorder. These conditions are thought to be linked to the disruptions in neurotransmitter production and homocysteine metabolism caused by MTHFR mutations (Gaysina et al., 2012; Gilbody et al., 2007).
Testing for MTHFR Mutations
There is disagreement whether we should test for MTHR variations or measure homocysteine levels. Geneticist Charis Eng (2020) writing for the Cleveland Clinic argues that "homocysteine levels determine our actions, not the MTHFR test results."
Homocysteine test graphic © luchschenF/Shutterstock.com.
However, homocysteine tests have several limitations when used to decide on folic acid supplementation. Intra-individual variability (Santhosh-Kumar et al., 1997), genetic factors (Crider et al., 2011), and baseline homocysteine levels (Miller et al., 2010) complicate the interpretation of these tests. When a physician believes genetic testing is more appropriate, it can detect these mutations using a simple blood test or a cheek swab. The test looks specifically for the presence of the C677T and A1298C mutations. Knowing whether you carry these mutations can help guide lifestyle and dietary choices, and in some cases, medical treatment. Graphic © Sailful52/Shutterstock.com.
The frequency of MTHFR mutations varies across populations. For instance, the C677T mutation is present in approximately 10-15% of Caucasians in its homozygous form (having two copies of the mutation), while up to 50% of the population may carry at least one copy of the mutation (heterozygous). The A1298C mutation is also relatively common, with similar prevalence rates depending on the population group (Wilcken et al., 2003). The empowerDX testing service provides very understandable results. The client had a family history for miscarriages, heart issues, and strokes before their 70s. Based on two MTHFR variants, they added a methylfolate supplement.
Dietary Changes and Methylfolate Supplementation
Dietary interventions can significantly manage the associated risks for individuals with MTHFR mutations. Since these mutations impair the body's ability to convert folate into its active form, consuming foods rich in folate, such as leafy greens, legumes, and fortified cereals, becomes essential. However, even with a folate-rich diet, those with MTHFR mutations may still struggle to get enough active folate. Graphic © Danijela Maksimovic/Shutterstock.com.
Supplementation with methylfolate, the active form of folate, is often recommended to address this. Methylfolate bypasses the need for conversion by the MTHFR enzyme, directly providing the body with the form of folate it needs to support DNA synthesis, neurotransmitter production, and other critical processes (Bailey & Gregory, 1999). This supplementation can help correct the folate deficiency and reduce homocysteine levels, lowering the risk of associated health problems.
Methylfolate May Modestly Benefit Treatment-Resistant Patients
Methylfolate supplementation has been shown to improve antidepressant response in patients with MDD who have partial or no response to standard antidepressants (Hoepner et al., 2021; Jain et al., 2019; Maruf et al., 2021). Preliminary randomized, controlled trials suggest that methylfolate may be beneficial for reducing symptoms of mania in bipolar disorder (Sylvia et al., 2012). Its effectiveness in bipolar depression has not been evaluated in randomized, controlled trials. Methylfolate has been associated with improvements in negative symptoms of schizophrenia, although its effects on positive and general symptoms are less clear (Roffman et al., 2017; Sakuma et al., 2018)
Summary
The MTHFR gene plays a pivotal role in maintaining overall health, particularly in the brain, by facilitating the conversion of folate into its active form and regulating homocysteine levels. Mutations in this gene, such as C677T and A1298C, can disrupt these processes, leading to an increased risk of psychological disorders and other health issues. Genetic testing is essential for detecting these mutations and can guide effective management strategies, including dietary changes and supplementation with methylfolate.
These interventions can help mitigate the negative effects of MTHFR mutations, ensuring that the body maintains sufficient levels of active folate and keeps homocysteine levels in check. Moreover, understanding the potential impact of MTHFR mutations on brain function highlights the importance of personalized approaches to health care. Individuals with MTHFR mutations can take proactive steps to protect their mental and physical health by integrating genetic testing, dietary management, and ongoing monitoring of brain activity.
Glossary
A1298C mutation: a common genetic variation in the MTHFR gene that reduces the enzyme's efficiency, affecting folate metabolism and increasing health risks.
active folate: the bioavailable form of folate that is necessary for DNA synthesis, repair, and neurotransmitter production.
amino acids: the building blocks of proteins, essential for various bodily functions.
B vitamins: a group of water-soluble vitamins, including folate, that are important for energy production and metabolic processes.
C677T mutation: a prevalent genetic alteration in the MTHFR gene that significantly decreases enzyme activity, leading to elevated homocysteine levels and potential health issues.
DNA synthesis: the process by which cells replicate their DNA, crucial for cell division and repair.
folate: a type of b vitamin essential for DNA synthesis, repair, and the production of neurotransmitters critical for brain function.
genetic testing: a medical test that identifies changes in chromosomes, genes, or proteins, such as the presence of MTHFR mutations.
homocysteine: an amino acid in the blood that, at elevated levels, is associated with an increased risk of cardiovascular and neurological diseases.
methionine: an essential amino acid produced from homocysteine conversion, necessary for protein synthesis and various metabolic processes.
methylenetetrahydrofolate reductase (MTHFR) gene: a gene that encodes the MTHFR enzyme, crucial for processing folate and regulating homocysteine levels in the body.
methylfolate: the active form of folate that can be directly utilized by the body for critical functions, often supplemented to bypass MTHFR enzyme deficiencies.
mutation: a change in a DNA sequence that can affect gene function, such as the C677T and A1298C mutations in the MTHFR gene.
neurodegenerative diseases: a group of disorders characterized by the progressive loss of neuron function, including conditions like Alzheimer's and Parkinson's disease.
neurotransmitters: chemical messengers in the brain, such as serotonin and dopamine, that transmit signals between nerve cells to regulate various bodily functions and emotions.
personalized medicine: a medical approach that tailors treatment and healthcare strategies to an individual's unique genetic makeup and specific health needs.
schizophrenia: a chronic mental health disorder characterized by distorted thinking, perceptions, emotions, and behavior, potentially linked to MTHFR gene mutations.
serotonin: a neurotransmitter involved in regulating mood, appetite, and sleep, with imbalances often associated with depression and anxiety disorders.
supplementation: the addition of nutrients or compounds, such as methylfolate, to the diet to address deficiencies and support overall health.
transformation of folate: the biochemical process by which the MTHFR enzyme converts dietary folate into its active form for use in various bodily functions.
References
Bailey, L. B., & Gregory, J. F. (1999). Folate metabolism and requirements. The Journal of Nutrition, 129(4), 779-782. https://doi.org/10.1093/jn/129.4.779
Clarke, R., Smith, A. D., Jobst, K. A., Refsum, H., Sutton, L., & Ueland, P. M. (1998). Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer's disease. Archives of Neurology, 55(11), 1449-1455. https://doi.org/10.1001/archneur.55.11.1449
Crider, K., Zhu, J., Hao, L., Yang, Q., Yang, T., Gindler, J., Maneval, D., Quinlivan, E., Li, Z., Bailey, L., & Berry, R. (2011). MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation.. The American Journal of Clinical Nutrition, 93(6), 1365-72 . https://doi.org/10.3945/ajcn.110.004671 Eng, C. (2020). A genetic test you don't need. Cleveland Clinic Health Essentials. https://health.clevelandclinic.org/a-genetic-test-you-dont-need Finkelstein, J. D. (2000). Pathways and regulation of homocysteine metabolism in mammals. Seminars in Thrombosis and Hemostasis, 26(3), 219-225. https://doi.org/10.1055/s-2000-8627
Gaysina, D., Cohen, S., & Craddock, N. (2012). Association of the MTHFR C677T polymorphism with depressive episodes in unipolar and bipolar mood disorders: Meta-analysis of 26 studies. The American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 159B(5), 560-572. https://doi.org/10.1002/ajmg.b.32064
Gilbody, S., Lewis, S., & Lightfoot, T. (2007). Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: A HuGE review. American Journal of Epidemiology, 165(1), 1-13. https://doi.org/10.1093/aje/kwj347
Hoepner, C., McIntyre, R., & Papakostas, G. (2021). Impact of supplementation and nutritional interventions on pathogenic processes of mood disorders: A review of the evidence. Nutrients, 13. https://doi.org/10.3390/nu13030767 Jain, R., Manning, S., & Cutler, A. (2019). Good, better, best: Clinical scenarios for the use of L-methylfolate in patients with MDD. CNS Spectrums, 25, 750 - 764. https://doi.org/10.1017/S1092852919001469 Kim, R., & Becker, R. (2003). Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies.. American Heart Journal, 146 6, 948-57 . https://doi.org/10.1016/S0002-8703(03)00519-2. Lucock, M. (2000). Folic acid: Nutritional biochemistry, molecular biology, and role in disease processes. Molecular Genetics and Metabolism, 71(1-2), 121-138. https://doi.org/10.1006/mgme.2000.3027
Maruf, A., Poweleit, E., Brown, L., Strawn, J., & Bousman, C. (2021). Systematic review and meta-analysis of l-methylfolate augmentation in depressive disorders. Pharmacopsychiatry. https://doi.org/10.1055/a-1681-2047 Poirier, V., Hebert, S., & Aubin, G. (2014). EEG analysis in children with autism spectrum disorder. Research in Developmental Disabilities, 35(10), 2518-2528. https://doi.org/10.1016/j.ridd.2014.06.020
Ray, J., Ray, J., & Laskin, C. (1999). Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review. Placenta, 20(7), 519-529. https://doi.org/10.1053/PLAC.1999.0417. Reynolds, E. H. (2002). Folic acid, ageing, depression, and dementia. BMJ, 324(7352), 1512-1515. https://doi.org/10.1136/bmj.324.7352.1512
Roffman, J., Petruzzi, L., Tanner, A., Brown, H., Eryilmaz, H., Ho, N., Giegold, M., Silverstein, N., Bottiglieri, T., Manoach, D., Smoller, J., Henderson, D., & Goff, D. (2017). Biochemical, physiologic, and clinical effects of L-methylfolate in schizophrenia: A randomized controlled trial. Molecular Psychiatry, 23, 316 - 322. https://doi.org/10.1038/mp.2017.41 Roffman, J. L., Weiss, A. P., Purcell, S., Doyle, A. E., Friedman, R. M., Smoller, J. W., & Goff, D. C. (2008). Contribution of the MTHFR gene to risk for schizophrenia and associated intermediate phenotypes. Schizophrenia Research, 100(1-3), 40-49. https://doi.org/10.1016/j.schres.2007.12.475
Sakuma, K., Matsunaga, S., Nomura, I., Okuya, M., Kishi, T., & Iwata, N. (2018). Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: A systematic review and meta-analysis. Psychopharmacology, 235, 2303 - 2314. https://doi.org/10.1007/s00213-018-4926-4 Santhosh-Kumar, C., Deutsch, J., Ryder, J., & Kolhouse, J. (1997). Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation. European Journal of Clinical Nutrition, 51, 188-192. https://doi.org/10.1038/sj.ejcn.1600385 Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., & Refsum, H. (2008). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS ONE, 3(3), e1923. https://doi.org/10.1371/journal.pone.0001923
Sylvia, L., Peters, A., Deckersbach, T., & Nierenberg, A. (2012). Nutrient-based therapies for bipolar disorder: A systematic review. Psychotherapy and Psychosomatics, 82, 10 - 19. https://doi.org/10.1159/000341309 Swatzyna, R. (2024). Personal communication regarding screening for MTHFR gene mutations. Wilcken, B., Bamforth, F., Li, Z., Zhu, H., Ritvanen, A., & Czeizel, A. E. (2003). Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): Findings from over 7000 newborns from 16 areas worldwide. Journal of Medical Genetics, 40(8), 619-625. https://doi.org/10.1136/jmg.40.8.619
Xuan, C., Li, H., Zhao, J., Wang, H., Wang, Y., Ning, C., Liu, Z., Zhang, B., He, G., & Lun, L. (2014). Association between MTHFR polymorphisms and congenital heart disease: A meta-analysis based on 9,329 cases and 15,076 controls. Scientific Reports, 4. https://doi.org/10.1038/srep07311.
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Dr. Inna Khazan's BCIA Introduction to biofeedback workshop will be offered in two parts this year.
Part 1 is entirely virtual, consisting of 20 hours (over 5 days) of live online instruction, home-study materials distributed prior to the live workshop, and written instructions for practical lab work to be completed during the week of the workshop or after its completion. Part 1 fulfills BCIA requirements for introduction to biofeedback didactic. Part 1 will take place on Zoom, November 4 - 8, 2024, 12 - 4pm EDT. Tuition is $1395.
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